Prosaposin: A Novel Biomarker of Prostate Cancer Progression in African Americans

Prosaposin：非裔美国人前列腺癌进展的新型生物标志物

• 批准号: 8147010
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 18.27万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2011-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147010
• 关键词: Affect; African American; Aftercare; Age; Apoptotic; Behavior; Benign; Biological; Biological Assay; Biological Markers; Cancer Etiology; Caucasians; Caucasoid Race; Cell Line; Cell Survival; Cells; Cessation of life; Characteristics; Clinical; Data; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gland; Gleason Grade for Prostate Cancer; Health Services Accessibility; In Vitro; Incidence; Indolent; Investigation; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; NOD/SCID mouse; Neoplasm Metastasis; Nude Mice; Organ; PC3 cell line; Patients; Pattern; Peptide Hydrolases; Phenotype; Pilot Projects; Primary Neoplasm; Prognostic Factor; Prostate; Proteins; RNA Interference; Radical Prostatectomy; Risk Factors; Sampling; Screening for Prostate Cancer; Screening procedure; Serum; Specimen; Staging; Staining method; Stains; TNM; Testing; Time; Tissues; Tumor Markers; Undifferentiated; Xenograft procedure; base; cancer cell; cancer diagnosis; cell motility; clinically significant; follow-up; implantation; improved; mRNA Expression; men; migration; mortality; novel; overexpression; prognostic; protein expression; public health relevance; racial difference; subcutaneous; tissue resource; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Prostate cancer (PCa), the second leading cause of cancer-related death in US men, presents the greatest racial disparity of any malignant disease in African Americans, with a 1.6-1.9 times higher incidence rate and 2 - 3 times higher mortality rate than Caucasians. PCa in African Americans presents with more advanced clinical stages and aggressive tumors. PCa biomarkers are needed to improve early detection of clinically significant tumors and to distinguish indolent or slow growing tumors from more aggressive ones. In our search for tumor markers, we cloned prosaposin (PSAP) as a secreted protein and discovered its overexpression in metastatic PCa cells and tissues. Previously, we demonstrated that PSAP and/or its active molecular derivatives increase migration and invasion and up regulate matrix-degrading proteolytic enzymes expression in PCa cells. In Caucasians, serum-PSAP levels are increased in metastatic PCa when compared to primary PCa or normal prostate tissues. In addition, there was no difference in serum-PSAP levels between organ-confined and locally-invasive tumors. In contrast to Caucasians, our pilot study in African Americans shows that a) tissue expression of PSAP is significantly higher in undifferentiated tumors with Gleason grade 4/5 pattern than in the differentiated tumors with Gleason grade d 3 or benign glands (BPH) and b) serum-PSAP levels are higher in locally invasive (stage III/IV) tumors than in the organ-confined (stage I/II) tumors which positively correlates with disease progression. Based on these observations, we hypothesized that PSAP contributes to PCa progression and has the characteristics of a novel biomarker discriminating the aggressive tumors from non- aggressive ones in African American patients. To test our hypothesis, we propose the following Aims: 1) Define the clinical significance of serum-PSAP as a marker of PCa progression or aggressiveness in African Americans; 2) Determine the association between tissue expression of PSAP and clinical and histopathological predictors or prognosticators of PCa progression or aggressiveness in African Americans; and 3) Determine the association between PSAP and invasive and metastatic phenotypes in PSAP-over expressed or -silenced African American PCa cells. We will use immunohistochemical analysis and sandwich-ELISA assays to quantify PSAP expression levels in a large pool of tissue and serum samples and to determine their association with clinicohistopathological predictors or prognosticators of PCa aggressiveness and progression in African Americans. We will also test the effect of increased or decreased PSAP expression on tumor growth rate and spontaneous metastatic ability in subcutaneous and orthotopic tumor xenografts in African American- derived PCa cells. At the conclusion of this proposal, we will have defined the clinical and histopathological significance of PSAP as a biomarker of PCa progression and/or aggressiveness in African Americans that could be further utilized in clinical development. PUBLIC HEALTH RELEVANCE: The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African American (AA) men are higher than in Caucasians. To improve early detection of clinically significant tumors and to discriminate indolent or slow growing tumors from more aggressive ones, reliable prognostic factors or biomarkers are needed. An in-depth investigation of our preliminary discovery of a high expression of prosaposin (PSAP) levels in locally invasive and/or metastatic PCa cells, tissues, and serum samples from AA men would provide us with the clinical and histopathological values of this molecule as a biomarker for PCa screenings, diagnoses, or post-treatment follow up in AAs.

描述（由申请人提供）：前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因，在非裔美国人中，任何恶性疾病的种族差异最大，发病率是白人的1.6-1.9倍，死亡率是白人的2 - 3倍。非裔美国人的PCa表现为更晚期的临床阶段和侵袭性肿瘤。需要PCa生物标志物来改善临床显著肿瘤的早期检测，并将惰性或缓慢生长的肿瘤与更具侵袭性的肿瘤区分开来。在我们寻找肿瘤标志物的过程中，我们克隆了鞘脂激活蛋白原（PSAP）作为一种分泌蛋白，并发现其在转移性前列腺癌细胞和组织中过表达。以前，我们证明，PSAP和/或其活性分子衍生物增加迁移和侵袭，并上调PCa细胞中基质降解蛋白水解酶的表达。在高加索人中，与原发性PCa或正常前列腺组织相比，转移性PCa中的血清PSAP水平升高。此外，器官局限性肿瘤和局部浸润性肿瘤之间的血清PSAP水平没有差异。与高加索人相比，我们在非裔美国人中的初步研究表明：a）PSAP在Gleason分级为4/5的未分化肿瘤中的组织表达显著高于Gleason分级为d 3或良性腺体（BPH）的分化肿瘤，和B）在局部浸润性肿瘤中血清PSAP水平更高。与器官局限性（I/II期）肿瘤相比，器官局限性（III/IV期）肿瘤与疾病进展呈正相关。基于这些观察结果，我们假设PSAP有助于PCa进展，并且具有区分非裔美国人患者中的侵袭性肿瘤与非侵袭性肿瘤的新型生物标志物的特征。为了验证我们的假设，我们提出以下目的：1）确定血清PSAP作为非裔美国人中PCa进展或侵袭性的标志物的临床意义; 2）确定PSAP的组织表达与非裔美国人中PCa进展或侵袭性的临床和组织病理学预测因子或预测因子之间的关联;和3）在PSAP过表达或沉默的非洲裔美国人PCa细胞中确定PSAP与侵袭性和转移性表型之间的关联。我们将使用免疫组化分析和ELISA法定量PSAP表达水平在一个大池的组织和血清样本，并确定其与临床组织病理学的预测因子或PCa的侵袭性和进展的预测因子在非洲裔美国人。我们还将测试PSAP表达增加或减少对非裔美国人来源的PCa细胞中皮下和原位肿瘤异种移植物中的肿瘤生长速率和自发转移能力的影响。在本提案结束时，我们将确定PSAP作为非裔美国人中PCa进展和/或侵袭性的生物标志物的临床和组织病理学意义，可进一步用于临床开发。 公共卫生相关性：非裔美国人（AA）男性前列腺癌（PCa）的发病率、死亡率和侵袭性均高于白人。为了改善临床显著肿瘤的早期检测，并区分惰性或缓慢生长的肿瘤与更具侵袭性的肿瘤，需要可靠的预后因子或生物标志物。对我们初步发现的局部侵袭性和/或转移性前列腺癌细胞、组织和AA男性血清样本中鞘脂激活蛋白原（PSAP）水平高表达的深入研究将为我们提供该分子作为前列腺癌筛查、诊断或AA治疗后随访的生物标志物的临床和组织病理学价值。